Neuroadaptations and drugs of abuse

Abstract

Neuroadaptations are anatomic or physiologic changes that attempt to maintain homeostasis and occur following the use of cocaine, methamphetamine (Meth), and 3,4-methylenedioxymethamphetamine (MDMA). Cocaine and Meth increase Central Nervous System (CNS) synaptic dopamine (DA) by increasing the release of DA into the synapse and binding to the DA reuptake transporter (DAT). The continued release of DA and prevention of reuptake results in supraphysiologic concentration of DA which stimulates postsynaptic receptors and causes euphoria or a “high”. Neuroadaptations in the CNS synapse (sch as a decrease in postsynaptic D2 receptro number) attempt to maintain homeostasis. The decreased number of D2 receptors provides fewer receptors to be stimulated by increased synaptic DA. Like cocaine, Meth increases synaptic DA, but Meth also increases cytoplasmic DA which causes CNS oxidative stress and neurotoxicity. The clinical impact of the oxidative stress is unknown. MDMA increases concentrations of synaptic serotonin (5-HT) by increasing the release of 5-HT and binding to the serotonin reuptake transporter (SERT). Neuroadaptive decrease in the number of 5-HT presynaptic autoreceptors (a regulator of synaptic 5-HT concentration) maintains homeostasis. MDMA also causes a decrease in serotonergic biochemical markers and neuronal axotomy in rats and nonhuman primates. Abstinence may allow reinnervation but the axonal regrowth pattern is abnormal. Whether axotomy and reinnervation also occur in humans is unknown. Conclusion: Neuroadaptations may be transient or permanent. The length of time of drug use or drug concentration needed to cause neuroadaptations is unknown, but some neuroadaptations begin shortly after initiation of drug use and are dependent on variables such as genetics and age of initiation of use. Understanding the concept of neuroadaptation and some specific neuroadaptations allows a better understanding of the interindividual variability in response to drugs of abuse.